This invention relates generally to a bioabsorbable marker having radiopaque constituents xe2x80x9cbioabsorbable-radiopaque markerxe2x80x9d for use on an implantable endoprosthesis such as a stent. The bioabsorbable marker includes dispersable radiopaque constituents which are not bioabsorbable or degradable, but are excreted from the body or stored in the body.
Implantable endoprostheses including stents, stent-grafts, and grafts are used in percutaneous transluminal coronary angioplasty and in other medical procedures to repair and support diseased or damaged arteries and body lumens. Grafts are implanted to cover or bridge leaks or dissections in vessels. Stent-grafts are stents which generally have a porous coating attachment. Unsupported grafts are porous tubes which are typically implanted by surgical cut-down.
In order to visualize the passage and placement of the implantable endoprosthesis in arteries and body lumens, many surgical procedures are performed with the aid of fluoroscopic angiography. The surgical delivery device and implantable endoprosthesis may be visualized if they are radiopaque and offer radiographic contrast relative to the body. For example, X-ray radiation may be used to visualize surgical delivery devices and deployment of the implant in the body. Also, radiographic contrast solution may be injected into the body lumen so that the lumen may be seen in the fluoroscopic image.
In order for the Implantable endoprosthesis to be radiopaque, it must be made from a material possessing radiographic density higher than surrounding host tissue and have sufficient thickness to affect the transmission of x-rays to produce contrast in the image. Reference is made to the clad composite stent shown in U.S. Pat. No. 5,630,840. An implantable endoprosthesis may be made of metals including tantalum, or platinum having relatively high radiographic densities. Other metals such as stainless steel, superalloys, nitinol, and titanium having lower radiographic densities may also be used. Reference is made to implantable devices shown in U.S. Pat. Nos. 4,655,771; 4,954,126; and 5,061,275.
An implantable polymeric endoprosthesis is generally radiolucent and does not possess sufficient radiographic density to be easily imaged by fluoroscopy. To improve the imaging of such polymeric materials, polymers may be mixed with radiopaque filler materials prior to molding or extruding in order to enhance the radiographic density. However, a disadvantage of using fillers with polymers is that changes in the properties of the polymer may occur. For example, the additions of fillers may reduce the strength or ductility of the polymer.
There is a need for an improved bioabsorbable-radiopaque marker for use in medical devices, particularly in temporary medical devices having low radiopacity. The need to improve the radiopacity of a relatively low radiopaque implantable endoprosthesis or to improve imaging in low radiopaque conditions is particularly important for surgery, micro-surgery, neuro-surgery, and conventional angioplasty procedures performed under fluoroscopy. Physicians are constantly being challenged to place small implants at specific intraluminal locations. Various devices having radiopacity are known in the art such as shown in U.S. Pat. Nos. 4,447,239; 5,354,257; and 5,423,849.
All documents cited herein, including the foregoing, are incorporated herein by reference in their entireties for all purposes.
Accordingly, there is a need for bioabsorbable-radiopaque markers for use on implantable endoprostheses in order to improve radiopacity and the locatability of an endoprosthesis during various medical procedures. Providing temporary radiopacity is especially advantageous for implantable endoprostheses having little or no radiopacity. The bioabsorbable-radiopaque markers allow radiographic identification of one or more locations of interest on an implantable endoprosthesis. Bioabsorbable-radiopaque markers in the fabric or covering materials of an implantable endoprosthesis are advantageous for indicating the location of the fabric or covering during implantation.
Alternative uses include threading the markers: adjacent a helical strand in the implantable endoprosthesis; circumferentially around the implantable endoprosthesis; or in a straight line in the axial direction of the implantable endoprosthesis. One or more bioabsorbable-radiopaque markers may be used on the implantable endoprosthesis having little or no radiopacity. After implantation, the bioabsorbable-radiopaque marker may be absorbed, dissolved, or excreted from the body so as not to effect the function of the endoprosthesis.
A disadvantage of certain permanent radiopaque markers is that they may compromise structural integrity, may not be biocompatible or biostable, and may be more thrombogenic than the implantable endoprosthesis.
The bioabsorbable-radiopaque marker of the present invention advantageously allows most any implantable endoprosthesis to have temporary radiopacity over a predetermined portion of its structure, and advantageously assists with proper positioning and locatability of the implantable endoprosthesis in a body lumen.
Use of the bioabsorbable-radiopaque marker is advantageous because the radiopaque property may be present only for a desired time period on an implantable endoprosthesis. For instance, once the implantable endoprosthesis is implanted, it may be more desirable to image with techniques such as ultrasound, magnetic resonance, and endoscopy and to avoid further radiation exposure to the patient. As the bioabsorbable polymer degrades, radiopaque material simultaneously or subsequently disperses into the body. The dispersion of the radiopaque material from the marker results in a loss of radiopacity in the marker. A predetermined rate of release of the radiopaque material may be designed into the bioabsorbable marker based on degradation of the polymer in the body or the design of the marker structure.
The bioabsorbable material in the bioabsorbable-radiopaque markers may include polymers or copolymers such as polylactide [poly-L-lactide (PLLA), poly-D-lactide (PDLA)], polyglycolide, polydioxanone, polycaprolactone, polygluconate, polylactic acid-polyethylene oxide copolymers, modified cellulose, collagen, poly(hydroxybutyrate), polyanhydride, polyphosphoester, poly(amino acids), poly(alpha-hydroxy acid) or related copolymers materials, each of which have a characteristic degradation rate in the body. For example, polyglycolide and polydioaxanone are relatively fast-bioabsorbing materials (weeks to months) and PLA is a relatively slow-bioabsorbing material (months to years). For a PLA member, mass degradation is completed with total absorption of the polymer endoprosthesis in about 1.5 to 3 years after implantation.
Bioabsorbable resins such as PLLA, PDLA, PGA and others are commerciallv available from several sources including PURAC America, Inc. of Lincolnshire, Ill. Radiopaque materials such as barium sulfate and bismuth trioxide are commercially available and compounded with the bioabsorbable resin by New England Urethane, Inc. of North Haven, Conn. The bioabsorbable resin or bioabsorbable-radiopaque resin may be extruded into filament by Albany International Research Co. of Mansfield, Mass.
The bioabsorption rate of the marker may be designed to be fast for applications where acute radiopacity is desired such as during positioning and placement of the implant. Alternatively, the bioabsorption rate may be designed to be slower for applications where the implant must be radiographically imaged for at least a portion of its functional time, for example, in implants where healing may take months. Other bioabsorption rates are also possible. The bioabsorption rate of the marker may be, tailored by controlling the type of bioabsorbable polymer; chemical composition of the bioabsorbable polymer; molecular weight of the bioabsorbable polymer; thickness and density of the bioabsorbable polymer; surface area of the marker, exit area for the radiopaque material, and design of the marker structure.
The degradation products from the bioabsorbable marker and the dispersed radiopaque material are metabolized, excreted, or stored by the body. Metabolism is the chemical process in living cells by which energy is provided for vital processes and activities and new material is assimilated to repair the waste. It is the sum of the processes by which a particular substance is handled in the living body. Excretion is separation and elimination or discharge from the blood or tissues of useless, superfluous, or harmful material that is eliminated from the body.
The biocompatibility of absorbable polymers during degradation depends upon the rate of accumulation and how well the surrounding tissue or fluid buffers or metabolizes the degradation products. If the products are metabolizable, the rate at which this will occur is dependent upon the blood circulation in the tissue. A well-vascularized lumen wall could buffer and metabolize degradation products as they are released from the implant. This biological process is important to minimize adverse tissue reaction to the degrading implant.
The degradation products from PLLA and PGA are lactic and glycolic acid, respectively, which are normally present in the human body. The acids are metabolized by cells around the implant. The metabolization process is a citrate cycle which converts the acids to carbon dioxide which is respirated out of the body.
The radiopaque agents added to the bioabsorbable marker are generally insoluble in the body and thus are not metabolizable. If these materials are trapped within tissue, the host generally reacts by encapsulation and acceptance of the biologically inactive particles. If the material is released from the implant into systemic circulation, it will migrate with fluid flow until being excreted or collected and stored by organs or tissue. The idea is to only have small amounts of the radiopaque substances in the implant by incorporating the discrete bioabsorbable-radiopaque marker rather than to load the entire implant with the radiopaque material. Minimization of the amount of radiopaque material which will be liberated from the marker upon absorption of the polymer must be considered when determining the loading percentage based on radiographic and mechanical properties.
To be radiopaque, the markers should include material having atomic elements of sufficiently high atomic number and be of sufficient thickness to provide sufficient radiopacity for imaging. The bioabsorbable-radiopaque marker may have one or more hollow, cavity, or porous portions wherein radiopaque material may be disposed.
Attenuation is the change in the number of photons in the incident x-ray beam due to the interaction with an absorber. To image an object implanted in the body, it would be desirable to have the object attenuate x-rays more than body tissue, bone, and fat so that the difference in contrast will be obvious in a radiograph. The difficulty in selecting a radiopaque material for surgical implants is that the material must have desirable radiographic characteristics and biocompatibility.
In order to make an implant more radiopaque, a substance which absorbs more x-rays can be deposited on or mixed in with the implant material. If the implant absorbs more x-rays than the surrounding medium (for example tissue in the body), it will be visible as a sharp change in contrast on an x-ray film or fluoroscopy image.
The fraction of x-ray energy transmitted through the absorber is quantitatively predicted by the following equation described in The Physics of Radiology, Fourth Ed., H. Johns, J. Cunningham, 1983, pp.137-142.
N=N0exe2x88x92xcexcx
N=number of photons transmitted through x
N0=number of photons in the incident beam
xcexc=linear attenuation coefficient of the absorber
x=absorber thickness
N/N0 would be the fraction of incident x-ray energy that is transmitted through the absorber. A more radiopaque material would have a lesser fraction of transmitted energy than a more radiolucent material. Therefore, to enhance the radiopacity of a material, such as the marker material, it would be desirable to select a material with high x-ray absorbing capability to minimize the fraction of transmitted energy. This radiopacity capability is proportional to the linear attenuation coefficient and the thickness of the absorber material. The higher the attenuation coefficient of the absorber material for a given thickness, the more radiopaque the absorber will be. The attenuation produced by an absorber is dependent upon the number of electrons and atoms present in the absorber. One way of quantifying this absorption characteristic is with the atomic attenuation coefficient which is directly proportional to the linear attenuation coefficient and the atomic number of the absorber element. Radiopacity is therefore generally proportional to the atomic number (number of electrons in the atom) of the material. Candidate materials for enhancing the radiopacity of surgical implants would have higher atomic numbers than the elements present in the body and would have to be biocompatible. The atomic number must be sufficiently high so that relatively small thickness of absorber material can be used in the body. Reference is also made to linear attenuation coefficient described in U.S. Pat. No. 5,628,787. Reference is made to Table 1 which describes a number of elements and their respective atomic numbers and certain linear attenuation coefficients.
The elements hydrogen, oxygen, carbon, and nitrogen are commonly found in the body and in polymers, so elements with higher atomic numbers than these should enhance the radiopacity of a polymer implant or marker. Tantalum, zirconium, titanium, barium, bismuth, and iodine are known to be non-toxic in certain concentrations and thus are candidate elements for enhancing radiopacity of a polymer marker in an implant. These elements can be added to the polymer in various loading percentages and the threshhold above which the loading causes unsatisfactory changes in the polymer characteristics can be determined through material and device testing. The elements which can be added in quantities sufficient to enhance radiopacity and maintain an acceptable level of polymer properties and which are biocompatible could be utilized in markers. The biocompatible elements with a range of atomic numbers of from about 22 to about 83 and having linear attenuation coefficients in the range of from about 5.46 to about 151.53 cmxe2x88x921 at 50 KeV should provide enough enhancement in radiopacity without excessive thickness being necessary to be useful in markers. These elements would include at least titanium, vanadium, chromium, iron, cobalt, nickel, copper, bromine, zirconium, niobium, molybdenum, silver, iodine, barium, tantalum, tungsten, platinum, gold, and bismuth. The preferred metallic elements for biocompatibility and radiopacity are titanium, zirconium, tantalum, and platinum. The preferred organic elements for biocompatibility and radiopacity are bromine, iodine, barium, and bismuth. Especially preferred elements are tantalum, platinum, barium, and bismuth because of their high atomic numbers and biocompatibility (atomic numbers from 56 to 83 and linear attenuation coefficients from about 50 to about 151.53). Tantalum and platinum are used as stent components and barium sulfate and bismuth trioxide are used as radiopaque enhancements for polymer catheters.
The bioabsorbable-radiopaque marker may be integrated into a subassembly or a finished implantable endoprosthesis during manufacture. Radiopaque elongate elements may be braided together with non-radiopaque bioabsorbable elongate elements to form a tubular braided stent, or the bioabsorbable and radiopaque elongate elements may be woven into the finished-braided stent.
The bioabsorbable-radiopaque marker would advantageously add temporary radiopacity to an implantable endoprosthesis such that the temporary marker would not require a medical procedure for removal from the patient.
In sum the invention relates to an implantable endoprosthesis and bioabsorbable-radiopaque marker system including an implantable endoprosthesis adapted to be disposed in a body lumen and at least one marker. The marker having a proximal end, a distal end, and a thickness. The marker including bioabsorbable material and radiopaque material and is disposed on or adjacent the endoprosthesis. The marker is adapted to degrade in vivo whereby the bioabsorbable material is metabolized through or excreted from the body and the radiopaque material is excreted from or stored in the body. The bioabsorbable material may include a polymer or copolymer. The bioabsorbable material may include poly-L-lactide, poly-D-lactide, polyglycolide, polydioxanone, polycaprolactone, and polygluconate, polylactic acid-polyethylene oxide copolymers, modified cellulose, collagen, poly(hydroxybutyrate), polyanhydride, polyphosphoester, poly(amino acids), poly (alpha-hydroxy acid) and combinations thereof. The radiopaque material may have a linear attenuation coefficient of from about 5.46 cmxe2x88x921 at 50 KeV to about 151.53 cmxe2x88x921 at 50 KeV. The marker may have an average thickness of from about 20 microns to about 500 microns and the radiopaque material includes at least one element with an atomic number of from about 22 to about 83. The radiopaque material may include barium sulfate, bismuth trioxide, bromine, iodine, iodide, titanium oxide, zirconium oxide, tantalum, and combinations thereof. The radiopaque material may be an oxide or salt material. One of the bioabsorbable material or radiopaque material may be coated or compounded with the other and the radiopaque material may have a linear attenuation coefficient of from about 5.46 cmxe2x88x921 at 50 KeV to about 151.53 cmxe2x88x921 at 50 KeV. The marker may have a weight percent of the radiopaque material in the bioabsorbable material of from about 1% to about 80%. The bioabsorbable material may consist of PLLA and the radiopaque material may consist of bismuth trioxide and the weight percent of the bismuth trioxide in the PLLA may be at least about 10%. The bioabsorbable material may consist of PLLA and the radiopaque material may be barium sulfate and the weight percentage of the barium sulfate in the PLLA may be at least about 10%. The marker may substantially degrades in less than about 3 years. xe2x80x9cSubstantial degradadation of the markerxe2x80x9d means that the marker has lost at least 50% of its structural strength. It is preferable that the marker lose about 100% of its structural strength. The bioabsorbable material may consist of polylactide and the radiopaque material may consist of barium sulfate, bismuth trioxide, iodine, iodide, and combinations thereof and the marker substantially degrades in from about 1 year to about 2 years. The bioabsorbable material may include poly-L-lactide, poly-D-lactide, polyglycolide, and combinations thereof and the radiopaque material may include barium sulfate, bismuth trioxide, bromine, iodine, iodide, and combinations thereof and the marker substantially degrades in from about 3 months to about 1 year. The bioabsorbable material may include polyglycolide, polygluconate, polydioxanone, and combinations thereof and the radiopaque material may include barium sulfate, bismuth trioxide, bromine, iodine, iodide, and combinations thereof and the marker substantially degrades in from about 1 week to about 3 months. The marker may be a mono-filament, multi-filament, thread, ribbon, suture, and combinations thereof. The marker may include one or more hollow, cavity, porous, and combinations thereof portions and the radiopaque material may be disposed therein. The marker may have radiopacity for a predetermined amount of time. The endoprosthesis may be a stent, stent-graft, graft, filter, occlusive device, or valve. The endoprosthesis may have a tubular, radially expandable structure and axially flexible structure including a plurality of the elongate elements which are interwoven in a braid-like configuration.
The invention also relates to an implantable endoprosthesis and bioabsorbable-radiopaque marker system including an implantable endoprosthesis adapted to be disposed in a body lumen and at least one elongated marker. The marker is adapted to be disposed on or adjacent the endoprosthesis. The marker includes a proximal end, distal end, thickness, bioabsorbable material, and a radiopaque material having a linear attenuation coefficient of from about 5.46 cmxe2x88x921 at 50 KeV to about 151.53 cmxe2x88x921 at 50 KeV. The marker has at least one hollow, cavity, or porous portion where the radiopaque material may be disposed. The bioabsorbable material at least partially contains the radiopaque material in the marker. The radiopaque material may be a liquid, solid, powder, gel, particle, or combinations thereof.
The invention also relates to a method of marking an implantable endoprosthesis including: disposing at least one elongate marker on or adjacent to at least a portion of an implantable endoprosthesis. The marker is from about 20 weight percent to about 99 weight percent of a bioabsorbable polymer and from about 1 weight percent to about 80 weight percent of a radiopaque material. The radiopaque material includes liquid or particles, the particles having an average diameter less than about 200 microns and a maximum diameter less than about 400 microns. The radiopaque material has a linear attenuation coefficient of from about 5.46 cmxe2x88x921 at 50 KeV to about 151.53 cmxe2x88x921 at 50 KeV; disposing the endoprosthesis and marker in a delivery system; inserting the delivery system in a body lumen; deploying the endoprosthesis and marker from the delivery system into a body lumen; and allowing the polymer to bioabsorb or excrete and the radiopaque material to subsequently or simultaneously at least partially disperses from the endoprosthesis.
The invention also relates to a temporary bioabsorbable-radiopaque marker including a marker having an average thickness less than about 500 microns and consisting of a bioabsorbable material and a radiopaque material, the radiopaque material having a linear attenuation coefficient of from about 5.46 cmxe2x88x921 at 50 KeV to about 151.53 cmxe2x88x921 at 50 KeV. The marker is adapted to be disposed in a body lumen and degrade in vivo. The marker may be elongate and have a proximal end and a distal end.
The invention also relates to a bioabsorbable-radiopaque marker including an elongate element adapted to be disposed in a body lumen and used as a surgical guide, the element including a bioabsorbable material, a radiopaque material, and combinations thereof. The element has a weight percent, W, of the radiopaque material in the bioabsorbable material, and an average thickness, T, over the length of the elongate element. The weight percent, W, is equal to about:
(i) [10+((950xc3x97T(measured in mm))xe2x88x92208.5)]xc2x15 for radiopaque material having atomic weight 20-100;
(ii) ((950xc3x97T(measured in mm))xe2x88x92208.5)xc2x15 for radiopaque material having atomic weight of 100 to 150 up to a maximum of 80 weight percentage; or
(iii) [((950xc3x97T(measured in mm))xe2x88x92208.5)xe2x88x9210]xc2x15 for radiopaque material having atomic weight greater than 150. The minimum W is about 1 and the maximum W is about 80.
The invention also relates to a marker including from about 20 weight percent to about 99 weight percent of a bioabsorbable polymer; and from about 1 weight percent to about 80 weight percent of a radiopaque material. The radiopaque material includes at least one of a liquid or particle having an average particle diameter less than about 8 microns and a maximum particle diameter less than about 10 microns. The radiopaque material has a linear attenuation coefficient of from about 5.46 cmxe2x88x921 at 50 KeV to about 151.53 cmxe2x88x921 at 50 KeV. For vascular system. The preferred average particle size is from about 3 microns to about 6 microns and a maximum particle size of 6 microns. For the digestive system, the average particle size may be from about 100 microns to about 150 microns and a maximum particle size of 400 microns.
Still other objects and advantages of the present invention and methods of construction of the same will become readily apparent to those skilled in the art from the following detailed description, wherein only the preferred embodiments are shown and described, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized, the invention is capable of other and different embodiments and methods of construction, and its several details are capable of modification in various obvious respects, all without departing from the invention. Accordingly, the drawing and description are to be regarded as illustrative in nature, and not as restrictive.